Toll-like receptors (TLRs) recognize specific molecular patterns present in molecules that are broadly shared by pathogens, but are structurally distinct from host molecules.1,2 The human genome includes 10 known TLRs.2 The ligands for these receptors are highly conserved microbial molecules such as lipopolysaccharides (LPS) (recognized by TLR4), lipopeptides (TLR2 in combination with TLR1 or TLR6), flagellin (TLR5), single stranded RNA (TLR7 and TLR8), double stranded RNA (TLR3), CpG motif-containing DNA (recognized by TLR9), and profilin present on uropathogenic bacteria (TLR11).3,4 TLR1, -2, -4, -5, and -6 respond to extracellular stimuli, while TLR3, -7, -8 and -9 respond to intracytoplasmic PAMPs.2 The activation of TLRs by their cognate ligands leads to activation of innate immune effector mechanisms, including the production of pro-inflammatory cytokines, and up-regulation of MHC molecules and co-stimulatory signals in antigen-presenting cells as well as activating natural killer (NK) cells. The consequence of activation of the innate immune system mobilizes and amplifies specific adaptive immune responses involving both T- and B-cell effector functions.5-7 Thus, TLR stimuli serve to link innate and adaptive immunity5 by eliciting both primary and anamnestic immune responses.
TLR7 agonists stimulate virtually all subsets of lymphocytes without inducing dominant proinflammatory cytokine responses (unlike TLR4-5 or -8 agonists, which can be proinflammatory and therefore may exert systemic toxicity).8 TLR7-active compounds therefore represent candidates as potential vaccine adjuvants and immune response modifiers.
In the 1970s and '80s a number of small molecules were synthesized and evaluated for antiviral activities owing to their pronounced Type I interferon (IFN-α and -β) inducing properties.12-16 The 1H-imidazo[4,5-c]quinolines were found to be good Type I IFN inducers in human cell-derived assays.17 Imiquimod is FDA approved for the treatment of basal cell carcinoma and actinic keratosis, and Gardiquimod is a another imidazoquinoline TLR7 agonist.18 Several years later the mechanistic basis of IFN induction by the imidazoquinolines was found to be a consequence of TLR7 engagement and activation.19 Certain imidazoquinoline compounds have been approved for use as antiviral agents as well as immune modulating compounds. However, the structure-activity relationship of the imidazoquinoline chemotype still remains largely unexplored and new, useful imidazoquinoline based compounds are still being developed.